Individuals diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) smoke more than the general population, initiate use at a younger age, and report more difficulty trying to quit. Moreover, recent evidence from our laboratory suggests the impulsivity and response inhibition inherent in ADHD play an important and unique role in the initiation of smoking behavior, and more pertinent to the aims of this project, in the maintenance of smoking and in relapse following attempts to quit. Though abstinence-induced changes in nicotinic and dopaminergic neurotransmission likely disrupt fronto-striatal and parietal circuits associated with response inhibition, little experimental work has been done to investigate possible mechanisms underlying abstinence-induced response inhibition deficits among either ADHD or non-ADHD smokers. Thus, the overarching goal of the present application is to use neuroimaging, neuropharmacological and molecular genetic techniques to study the neurobiological basis of abstinence-induced deficits in response inhibition in ADHD and non-ADHD smokers. Twenty smokers with ADHD and 20 smokers without ADHD will undergo imaging during a Go/No-Go task under the following conditions: 1) smoking as usual, 2) 24 hr smoking abstinence, and 3) 24 hr smoking abstinence + methylphenidate (MPH). We hypothesize that compared to smoking as usual, 24 hr smoking abstinence will result in decrements in response inhibition and disruption of task-related brain activation. These effects will be greater in ADHD as compared to non-ADHD smokers. We further hypothesize that MPH administration during abstinence will restore performance and brain indices of response inhibition and that the magnitude of the effect of MPH will be greater among smokers with ADHD. In addition to the above aims, we will preliminarily evaluate the moderating effects of the dopamine receptor D4 7-repeat allele on task-related brain activation following smoking abstinence and MPH administration. The findings of this study will shed new light on the neuropharmacological mechanisms underlying comorbid ADHD and nicotine dependence. Moreover, the proposed project will provide a substantive neurobiological foundation on which new treatments for this comorbidity can be developed. Finally, since impulsivity and related constructs have been strongly associated with smoking and other addictions in non-clinical samples, our approach will shed light on substance use and abuse more broadly.PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. and individuals with Attention Deficit Hyperactivity Disorder (ADHD) smoke at disproportionately high rates. Impulsivity and the related problem of inhibiting over-learned behaviors may contribute to greater smoking among individuals with ADHD. The proposed research will lead to a better understanding of the neural and genetic basis of comorbid ADHD and nicotine dependence and inform the development of new treatments.